Lysostaphin is a 27 kDa enzyme that cuts the pentaglycine cross-link in the cell wall peptidoglycan of Staphylococcus aureus. We have shown that lysostaphin is extremely effective in treating S. aureus infections in animal models and that in the presence of low levels of beta-Iactam antibiotics the development of resistance to lysostaphin is not seen in S. aureus. However, in animal models, infused lysostaphin is rapidly cleared from the circulation, and repeated administration induces the production of anti-Iysostaphin antibodies that could reduce its therapeutic effectiveness. The aim of this project is to improve the circulating half-life of lysostaphin. We propose to develop poly(ethyleneglycol)-conjugated lysostaphin that retains its bactericidal and therapeutic activity and shows reduced clearance by glomerular filtration and other routes and reduced immunogenicity. Improving the half-life of lysostaphin in circulation should reduce both the dosing quantity and frequency required to maintain plasma concentrations above therapeutically effective levels. Maintaining prolonged high levels of lysostaphin may also result in more rapid clearance of bacterial infections. Lysostaphin promises to be an invaluable tool to healthcare professionals in combating the occurrence of nosocomial S. aureus infections (as a nasal cream) and in treating topical and systemic S. aureus infections, including S. aureus endocarditis. [unreadable] [unreadable]